KR102373590B1 - Novel nanoparticles using anionic polymers, preparation method and composition thereof - Google Patents

Abstract

The present invention relates to novel nanoparticles using negative ionic polymers, a manufacturing method thereof, a composition thereof, etc. The present invention can be applied to a method for necrosis of cancer cells by inducing an embolism effect by blocking major blood vessels that supply nutrients to cancer cells, thereby being able to be used to treat cancer patients.

Description

Novel nanoparticles using anionic polymers, their manufacturing method and composition {Novel nanoparticles using anionic polymers, preparation method and composition thereof}

The present invention relates to novel nanoparticles and manufacturing methods using anionic polymers, and the present invention is used in a method of necrosis of cancer cells by inducing an embolism effect by blocking major blood vessels that supply nutrients to cancer cells to treat cancer patients. can be used

Liver cancer is a malignant tumor with a poor prognosis that ranks second in Korea and third in the world among the causes of death due to carcinoma. In more than 70% of liver cancer patients, curative surgery is impossible, and even if radical resection is performed, the probability of recurrence at another site within 5 years is more than 50%. The probability of responding to systemic chemotherapy in advanced liver cancer is very low, within 10%, and various image-guided therapies have been developed as an alternative to non-surgical treatment methods. As image-guided therapy applied to liver cancer, two are representative. One is transarterial chemoembolization (TACE), a treatment in which an anticancer agent is locally injected into liver cancer through the hepatic artery and embolization of the hepatic artery is performed, and the other is One is radiofrequency ablation (RFA).

More than 95% of the blood flow supplied to liver cancer tissue is delivered to the hepatic artery, but more than 75% of the blood flow to the surrounding healthy tissue is delivered to the portal vein and only 25% to the hepatic artery. is a treatment

TACE is usually repeated 3 to 4 times a year, so it is necessary to ensure that the administered material is safe. Drugs mainly used for conventional arterial embolization are doxorubicin, cisplatin, epirubicin, mitoxantrone, and mitomycin C. These anticancer drugs cannot be dissolved directly in a water-insoluble contrast medium. It is formulated and used in the form of an oil-in-water or water-in-oil type emulsion homogeneously dispersed in a water-insoluble contrast agent (iodized oil) such as Since phase separation occurs after a certain period of time, this emulsion is prepared and used immediately before administration to the patient, chemical embolization is performed, and gelatin sponge particles are additionally administered to promote ischemic necrosis of cancer tissue and prevent drug loss. However, since the administered emulsion undergoes phase separation within a short time after administration and the anticancer agent is absorbed at once, the antitumor effect is not continuous, and there is a possibility that side effects may occur due to systemic exposure. In addition, most cytotoxic anticancer drugs administered to TACE are metabolized in the liver, so they may exhibit hepatotoxicity. For this reason, patients show postembolization syndrome and have difficulty in daily living, so hospitalization is inevitable for 2-3 days, resulting in high medical costs.

Chemical embolic particles (drug eluting beads, DEB), which have been selectively used recently, are made of non-absorbable polyvinyl alcohol, etc., and are administered by adsorbing drugs to embolic particles in an ion exchange method. The particle size ranges from 40 to 900 μm. . Compared to droplets of emulsion, the range of particles is homogeneous, reproducible, and the drug is slowly released, so the systemic exposure of the drug is small. However, since the drug is not completely released after administration, less than 50% is released until 28 days after administration, and about 90% is released after 90 days, so the drug is relatively slowly accumulated in the cancer tissue at a high concentration. In addition, it takes more than 1 to 2 hours to adsorb the drug, and the particles remain in the body even after the drug is completely released due to non-absorption, so it can cause necrosis of normal tissues, it can be difficult to repeat TACE treatment, and there is a risk of cancer recurrence. There is this. In addition, compared to the existing TACE method, the cost of the drug is high, and the patient's cost burden is high.

Therefore, there is a demand for the development of nanoparticles that have low toxicity and are compatible with the living body, and that can quickly and efficiently deliver a target drug to microvessels.

The Korean Journal of Hepatology 2010 ; 16:242-246

The present inventors have made diligent efforts to provide biocompatible nanoparticles and a method for manufacturing the same that compensate for the problems of microbeads and inorganic nanoparticles. As a result, after forming a W/O emulsion using an anionic polymer, microparticles from the oil phase After separation and purification, an object of the present invention is to provide a method for preparing nanoparticles using a high-pressure homogenizer or mill (bead or roll) equipment.

Accordingly, an object of the present invention is nanoparticles comprising an anionic polymer and a trivalent metal compound salt; and

To provide a composition for treating vascular embolism and cancer comprising a cationic drug as an active ingredient.

Another object of the present invention is to provide a method for preparing nanoparticles comprising an anionic polymer and a trivalent metal compound salt comprising the following steps.

Forming an emulsion by mixing a solution in which an aqueous phase in which an anionic polymer is dissolved in an oil phase; and a solution in which a nonionic surfactant is dissolved in the aqueous phase;

forming microparticles by adding an aqueous solution of a trivalent metal compound salt to the emulsion; and

Reducing the particle size to a nano level by using at least one selected from the group consisting of a high pressure homogenizer, a bead mill and a roll mill for the microparticles.

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.

The nanoparticles according to the present invention are composed of carboxymethyl cellulose, which is a cellulose-based anionic polymer, and dextran, which has biodegradable properties, and are characterized by using a cross-linking agent to increase aqueous phase stability. It is biocompatible and can deliver drugs down to microvessels.

Accordingly, the present invention relates to nanoparticles comprising an anionic polymer and a trivalent metal compound salt; and

It provides a composition for treating vascular embolism and cancer comprising a cationic drug as an active ingredient.

In one embodiment of the present invention, the anionic polymer is carboxymethyl cellulose or a salt thereof; dextran sulfate or a salt thereof; And it may be selected from the group consisting of mixtures thereof, but is not limited thereto.

In another embodiment of the present invention, the nanoparticles may include, but are not limited to, carboxymethyl cellulose and dextran sulfate.

In another embodiment of the present invention, the carboxymethyl cellulose and dextran sulfate may be included in a mass ratio of 0.5 to 20: 1, but is not limited thereto.

In another embodiment of the present invention, the trivalent metal compound salt is iron (III) chloride, aluminum chloride, iron nitrate [Fe(NO ₃ ) ₃ ], aluminum nitrate [Al(NO ₃ ) ₃ ], iron acetate [Fe (CH ₃ COO) ₃ ], aluminum acetate [Al(CH ₃ COO) ₃ ], and iron perchlorate [Fe(ClO ₄ ) ₃ ] It may be at least one selected from the group consisting of, but is not limited thereto.

In another embodiment of the present invention, the cationic drug is doxorubicin, procainamide, digoxin, quinidine, trimethoprim, cimetidine, vancomycin (vancomycin), Irinotecan, daunorubicin, epirubicin, diphenhydramine, memantine, oxycodone, pyrilamine and tramadol ( tramadol) may be one or more selected from the group consisting of, but is not limited thereto.

In another embodiment of the present invention, the cationic drug may be loaded onto the nanoparticles, but is not limited thereto.

In another embodiment of the present invention, the composition may be an emulsion formulation, but is not limited thereto.

In another embodiment of the present invention, the cationic drug and nanoparticles may be included in a mass ratio of 1 to 1 to 10, but is not limited thereto.

In another embodiment of the present invention, it may further include an embolic material, but is not limited thereto.

In another embodiment of the present invention, the embolic material may be iodized oil, but is not limited thereto.

In another embodiment of the present invention, the iodized oil may be at least one selected from the group consisting of iodized oil derived from poppy fruit, iodized oil derived from soybean, and ethiodol, but is not limited thereto.

In another embodiment of the present invention, the nanoparticles may have a diameter of 10 to 500 nm, but is not limited thereto.

In addition, the present invention provides a method for preparing nanoparticles comprising an anionic polymer and a trivalent metal compound salt, comprising the following steps.

Forming an emulsion by mixing a solution in which an aqueous phase in which an anionic polymer is dissolved in an oil phase; and a solution in which a nonionic surfactant is dissolved in the aqueous phase;

forming microparticles by adding an aqueous solution of a trivalent metal compound salt to the emulsion; and

Reducing the particle size to a nano level by using at least one selected from the group consisting of a high pressure homogenizer, a bead mill and a roll mill for the microparticles.

In one embodiment of the present invention, the oil phase may be selected from the group consisting of mineral oil, vegetable oil, medium chain triglycerides, and mixtures thereof, but is not limited thereto.

In another embodiment of the present invention, the nonionic surfactant is polyvinyl alcohol, polyalkylene glycol, polyvinyl pyrrolidone, alkyl polyglycoside, t-octylphenoxy polyethoxy ethanol, poloxamer, polysorbate, poly(N-vinylacetamide), polyvinyl buty Ral (polyvinyl butyral), and may be selected from the group consisting of mixtures thereof, but is not limited thereto.

In another embodiment of the present invention, the manufacturing method may further include a step of dissolving the microparticles by using an organic solvent to separate the precipitate and remove impurities and oil after precipitation by standing still in a separatory funnel However, the present invention is not limited thereto.

In another embodiment of the present invention, the organic solvent may be one or more selected from the group consisting of alkyl alcohols, ketones, acetonitrile, tetrahydrofuran, and mixtures thereof, but is not limited thereto.

In another embodiment of the present invention, the method may further include, but is not limited to, separating or purifying and washing the microparticles from the mixed solution containing the microparticles and dissolving impurities and oil.

In another embodiment of the present invention, the separation or purification of the microparticles may be performed by a centrifuge or a filter, but is not limited thereto.

In another embodiment of the present invention, the washing may be selected from the same organic solvent or the group of solvents mentioned above, but is not limited thereto.

In another embodiment of the present invention, for the washing, distilled water, water for injection, sucrose, mannitol or sodium chloride, etc. may be used in the washing after washing with the organic solvent. it is not

In another embodiment of the present invention, the method may further include, but is not limited to, redispersing the purified microparticles in an aqueous phase and then reducing the particle size using a particle size reduction equipment.

In another embodiment of the present invention, the redispersed aqueous phase may be selected from an aqueous solvent in which distilled water, water for injection, sucrose, mannitol or sodium chloride are dissolved, and the group thereof, but is not limited thereto.

In another embodiment of the present invention, the particle size reduction equipment may be selected from a high pressure homogenizer, a bead mill, a roll mill, and the group thereof, but is not limited thereto.

In addition, the present invention provides a method for preparing the composition for treating vascular embolism and cancer, comprising the following steps.

Forming an emulsion by mixing a solution in which an aqueous phase in which an anionic polymer is dissolved in an oil phase; and a solution in which a nonionic surfactant is dissolved in the aqueous phase;

forming microparticles by adding an aqueous solution of a trivalent metal compound salt to the emulsion;

preparing nanoparticles by reducing the particle size to a nano level using at least one selected from the group consisting of a high pressure homogenizer, a bead mill and a roll mill for the microparticles; and

mixing the cationic drug with the nanoparticles.

In addition, the present invention is nanoparticles comprising an anionic polymer and a trivalent metal compound salt; and

Provided is a vascular embolism and cancer treatment use of a composition comprising a cationic drug as an active ingredient.

In addition, the present invention is nanoparticles comprising an anionic polymer and a trivalent metal compound salt; and

It provides a method for treating vascular embolism and cancer comprising administering to an individual a composition comprising a cationic drug as an active ingredient.

In addition, the present invention is nanoparticles comprising an anionic polymer and a trivalent metal compound salt; and

It provides the use of a composition comprising a cationic drug as an active ingredient for the manufacture of a vascular embolism and cancer treatment agent.

The present invention provides a novel manufacturing method of nanoparticles that are useful for the delivery of cationic drugs, have low toxicity and are biocompatible, and can deliver drugs to microvessels, and the novel manufacturing method according to the present invention is industrially mass-produced. It has the effect of enabling production.

1 shows an image of whether the reaction solution is changed during the reaction of an anionic polymer and calcium chloride (CaCl ₂ ).
Figure 2 shows an optical microscopic image of the solid produced through the composition 2 of Example 1-2, <reactivity test 2>.
3 shows an image of microparticles prepared through the reaction of an anionic polymer and iron chloride according to the composition 2 of Example 3 and Table 3.
4 shows the results of measuring the particle distribution of nanoparticles prepared using a bead mill using dynamic light scattering (DLS).
5 shows a TEM measurement image of nanoparticles prepared using a bead mill.
6 is a graph showing the dissolution graph of the drug after loading the cationic drug (doxorubicin hydrochloride).
7 shows the results of measuring the cell viability in Huh7 cells.
8 shows an optical microscope image of an emulsion of a cationic drug-loaded nanoparticle suspension solution and Lipiodol ultra solution.
Figure 9 shows the microcatheter passing images of each suspension using 5%-sucrose and 15%-mannitol as drug-loaded aqueous suspensions and a mixed emulsion of Lipiodol ultra solution.

The nanoparticles according to the present invention are composed of carboxymethyl cellulose, which is a cellulose-based anionic polymer, and dextran, which has biodegradable properties, and are characterized by using a cross-linking agent to increase aqueous phase stability. It is biocompatible and can deliver drugs down to microvessels.

Accordingly, the present invention relates to nanoparticles comprising an anionic polymer and a trivalent metal compound salt; and

It provides a composition for treating vascular embolism and cancer comprising a cationic drug as an active ingredient.

In one embodiment of the present invention, the anionic polymer is carboxymethyl cellulose or a salt thereof; dextran sulfate or a salt thereof; And it may be selected from the group consisting of mixtures thereof, but is not limited thereto.

In another embodiment of the present invention, the nanoparticles may include, but are not limited to, carboxymethyl cellulose and dextran sulfate.

In another embodiment of the present invention, the carboxymethyl cellulose and dextran sulfate are 0.5 to 20: 1, 0.5 to 15: 1, 0.5 to 10: 1, 0.5 to 5: 1, 0.5 to 4: 1, 0.5 to 2:1, 0.5-1:1, about 1:1, 0.5-3:1, 1-3:1, 1.5-2.5:1, about 2:1, 1-5:1, 2-5:1, 3 to 5: 1, 3.5 to 4.5: 1, 4 to 5: 1 or about 4:1, 1 to 10, 1 to 9: 1, 3 to 9: 1, 4 to 9: 1, 5 to 9: 1 , 6 to 9: 1, 7 to 9: 1, 8 to 9: 1, 7.5 to 8.5: 1, or may be included in a mass ratio of about 8: 1, but is not limited thereto.

In another embodiment of the present invention, the carboxymethyl cellulose and dextran sulfate may be preferably included in a mass ratio of 8: 1, 4: 1, 2: 1, or 1: 1, but is limited thereto not.

In another embodiment of the present invention, the trivalent metal compound salt is iron (III) chloride, aluminum chloride, iron nitrate [Fe(NO ₃ ) ₃ ], aluminum nitrate [Al(NO ₃ ) ₃ ], iron acetate [Fe (CH ₃ COO) ₃ ], aluminum acetate [Al(CH ₃ COO) ₃ ], and iron perchlorate [Fe(ClO ₄ ) ₃ ] It may be at least one selected from the group consisting of, but is not limited thereto.

In another embodiment of the present invention, the cationic drug is doxorubicin, procainamide, digoxin, quinidine, trimethoprim, cimetidine, vancomycin (vancomycin), Irinotecan, daunorubicin, epirubicin, diphenhydramine, memantine, oxycodone, pyrilamine and tramadol ( tramadol) may be one or more selected from the group consisting of, but is not limited thereto.

In another embodiment of the present invention, the cationic drug and nanoparticles are 1:1 to 10, 1:1 to 9, 1:1 to 8, 1:1 to 7, 1:1 to 6, 1:1 to 5, 1:1 to 4, 1:1 to 3, 1:1 to 2.5, 1:2 to 2.5, or 1:1 to 1.5 may be included in a mass ratio of, but is not limited thereto.

In another embodiment of the present invention, the cationic drug and nanoparticles are 1:1 to 10, 1:1 to 9, 1:1 to 8, 1:1 to 7, 1:1 to 6, 1:1 to 5, 1:1 to 4, 1:1 to 3, 1:1 to 2.5, or 1:2 to 2.5 or 1:1 to 1.5 may be included in a dry weight ratio of, but is not limited thereto.

In another embodiment of the present invention, it may further include an embolic material, but is not limited thereto.

In another embodiment of the present invention, the embolic material may be iodized oil, but is not limited thereto.

In another embodiment of the present invention, the iodized oil may be at least one selected from the group consisting of iodized oil derived from poppy fruit, iodized oil derived from soybean, and ethiodol, but is not limited thereto. The iodized oil derived from the poppy fruit may use Lipiodol as a product name, but is not limited thereto.

In another embodiment of the present invention, the nanoparticles are 10-500 nm, 10-400 nm, 10-300 nm, 10-250 nm, 10-200 nm, 10-180 nm, 10-160 nm, 10- 150 nm, 10-140 nm, 30-500 nm, 30-400 nm, 30-300 nm, 30-250 nm, 30-200 nm, 30-180 nm, 30-160 nm, 30-150 nm, 30- 140 nm, 50 to 500 nm, 50 to 400 nm, 50 to 300 nm, 50 to 250 nm, 50 to 200 nm, 50 to 180 nm, 50 to 160 nm, 50 to 150 nm, 50 to 140 nm, 70 to It may have a diameter of 500 nm, 70 to 400 nm, 70 to 300 nm, 70 to 250 nm, 70 to 200 nm, 70 to 180 nm, 70 to 160 nm, 70 to 150 nm, 70 to 140 nm, However, the present invention is not limited thereto.

In another embodiment of the present invention, the cationic drug may be loaded in a form bound to anions present on the inside and surface of the nanoparticles.

In another embodiment of the present invention, the vascular embolization is arterial chemoembolization (TACE, Transarterial chemoembolization), and an anticancer agent is injected into an artery going to the cancerous tissue, and the embolic is used to block the nutrient supply to the cancerous tissue to treat cancer. could be a way to do it.

In another embodiment of the present invention, the cancer includes angiogenesis-dependent, preferably at least one selected from the group consisting of liver cancer, ovarian cancer, breast cancer and non-small cell lung cancer, and more preferably liver cancer. After binding the cationic drug to the nanoparticles according to an embodiment of the present invention, a stable emulsion can be formed when mixed with iodized oil, and the embolism effect can be increased by injecting the emulsion into the hepatic artery blood vessel.

The composition of the present invention may be provided in the form of an emulsion, but is not limited thereto.

The composition of the present invention is characterized in that it is administered within 0 to 2 hours, preferably 0 to 1 hour after preparation, and stability as the movement of the drug in the nanoparticles is kept low for a long time compared to the composition used in conventional chemical embolization. this is excellent

In the present invention, the composition including the nanoparticles and the cationic drug and the embolic material may be mixed using a mixing method using a 3-way cock, a method using ultrasound, etc., but is not limited thereto .

In addition, the present invention provides a method for preventing or treating vascular embolism and cancer comprising administering the composition to a subject.

The content of the nanoparticles and the cationic anticancer agent in the composition of the present invention can be appropriately adjusted depending on the symptoms of the disease, the degree of progression of the symptoms, the condition of the patient, etc., for example, 0.0001 to 99.9% by weight, or 0.001 based on the total weight of the composition to 50% by weight, but is not limited thereto. The content ratio is a value based on the dry amount from which the solvent is removed.

The pharmaceutical composition according to the present invention may further include suitable carriers, excipients and diluents commonly used in the preparation of pharmaceutical compositions. The excipient may be, for example, at least one selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, an adsorbent, a humectant, a film-coating material, and a controlled-release additive.

Carriers, excipients and diluents that may be included in the pharmaceutical composition according to the present invention include lactose, dextrose, sucrose, oligosaccharide, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

In the case of formulation, it is prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants.

As additives for the liquid formulation according to the present invention, water, diluted hydrochloric acid, diluted sulfuric acid, sodium citrate, monostearate sucrose, polyoxyethylene sorbitol fatty acid esters (Twinester), polyoxyethylene monoalkyl ethers, lanolin ethers, Lanolin esters, acetic acid, hydrochloric acid, aqueous ammonia, ammonium carbonate, potassium hydroxide, sodium hydroxide, prolamine, polyvinylpyrrolidone, ethyl cellulose, sodium carboxymethyl cellulose, etc. can be used.

In the syrup according to the present invention, a sucrose solution, other sugars or sweeteners may be used, and if necessary, a fragrance, colorant, preservative, stabilizer, suspending agent, emulsifying agent, thickening agent, etc. may be used.

Purified water may be used in the emulsion according to the present invention, and if necessary, an emulsifier, preservative, stabilizer, fragrance, etc. may be used.

Suspending agents such as acacia, tragacantha, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium alginate, hydroxypropylmethylcellulose, HPMC 1828, HPMC 2906, HPMC 2910 may be used in the suspending agent according to the present invention. and, if necessary, surfactants, preservatives, stabilizers, colorants, and fragrances may be used.

The injection according to the present invention includes distilled water for injection, 0.9% sodium chloride injection solution, ring gel injection solution, dextrose injection solution, dextrose + sodium chloride injection solution, PEG (PEG), lactated ring gel injection solution, ethanol, propylene glycol, non-volatile oil-sesame oil , solvents such as cottonseed oil, peanut oil, soybean oil, corn oil, ethyl oleate, isopropyl myristate, and benzene benzoate; Solubilizing aids such as sodium benzoate, sodium salicylate, sodium acetate, urea, urethane, monoethyl acetamide, butazolidine, propylene glycol, tweens, nijeongtinamide, hexamine, and dimethyl acetamide; Weak acids and their salts (acetic acid and sodium acetate), weak bases and their salts (ammonia and ammonium acetate), organic compounds, proteins, buffers such as albumin, peptone, gum; isotonic agents such as sodium chloride; sodium bisulfite (NaHSO ₃ ) carbon dioxide gas, sodium metabisulfite (Na ₂ S ₂ O ₃ ), sodium sulfite (Na ₂ SO ₃ ), nitrogen gas (N ₂ ), stabilizers such as ethylenediaminetetraacetic acid; sulphating agents such as sodium bisulfide 0.1%, sodium formaldehyde sulfoxylate, thiourea, disodium ethylenediaminetetraacetate, acetone sodium bisulfite; analgesic agents such as benzyl alcohol, chlorobutanol, procaine hydrochloride, glucose, and calcium gluconate; suspending agents such as SiMC sodium, sodium alginate, Tween 80, or aluminum monostearate.

The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is determined by the type, severity, drug activity, and type of the patient's disease; Sensitivity to the drug, administration time, administration route and excretion rate, treatment period, factors including concurrent drugs and other factors well known in the medical field may be determined.

The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or may be administered in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. In consideration of all of the above factors, it is important to administer an amount capable of obtaining the maximum effect with a minimum amount without side effects, which can be easily determined by a person skilled in the art to which the present invention pertains.

The pharmaceutical composition of the present invention is determined according to the type of drug as an active ingredient along with several related factors such as the disease to be treated, the route of administration, the patient's age, sex, weight, and the severity of the disease.

In the present invention, "individual" means a subject in need of treatment for a disease, and more specifically, human or non-human primates, mice, rats, dogs, cats, horses, cattle, etc. It may be a mammal of, but is not limited thereto.

In the present invention, "administration" means providing a predetermined composition of the present invention to an individual by any suitable method.

In the present invention, “prevention” means any action that suppresses or delays the onset of a target disease, and “treatment” means that the target disease and its metabolic abnormalities are improved or It means all actions that are beneficially changed, and “improvement” means all actions that reduce the desired disease-related parameters, for example, the degree of symptoms by administration of the composition according to the present invention.

In addition, the present invention provides a method for preparing nanoparticles comprising an anionic polymer and a trivalent metal compound salt, comprising the following steps.

i) forming an emulsion by mixing a solution in which an aqueous phase in which an anionic polymer is dissolved in an oil phase is added; and a solution in which a nonionic surfactant is dissolved in the aqueous phase;

ii) adding an aqueous solution of a trivalent metal compound salt to the emulsion to form microparticles; and

iii) reducing the particle size to a nano level by using at least one selected from the group consisting of a high pressure homogenizer, a bead mill and a roll mill for the microparticles.

Matters relating to the composition may be applied to the present manufacturing method.

The step i) may include one or more selected from the group consisting of the following steps a) to d), but is not limited thereto.

The step ii) may include the following steps e) and/or f), but is not limited thereto.

The step iii) may include the following step l), but is not limited thereto.

The manufacturing method of the nanoparticles may include a step of stirring so that each component is uniformly mixed between each step, but is not limited thereto.

It may include, but is not limited to, h) separating the microparticles from the oil phase between steps ii) and iii).

Between steps ii) and iii), i) adding an organic solvent to a solution containing microparticles to remove residual oil and side-reactants, but is not limited thereto.

In the present invention, the emulsion may be in the form of W/O, but is not limited thereto.

The W/O emulsion has an aqueous and oil phase ratio of 1:1 to 50, 1:1 to 40, 1:1 to 30, 1:1 to 20, 1:1 to 15, 1:1 to 10, 1: 1 to 9, 1:1 to 8, 1:1 to 7, 1:1 to 6, 1:2 to 6, 1:3 to 6, 1:2 to 5, 1:3 to 5, 1:50, can be 1:40, 1:30, 1:20, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, or 1:2 However, the present invention is not limited thereto. In the present invention, the higher the ratio of the oil, the better the emulsion can be formed, but the optimal ratio for using the minimum oil may be preferably about 1:4.

In the present invention, the method may further include, but is not limited to, separating or purifying and washing microparticles from a mixed solution containing microparticles and dissolving impurities and oil.

In the present invention, the manufacturing method may further include the step of dissolving the microparticles in a separatory funnel by allowing them to settle and then dissolving them using an organic solvent to separate the precipitate and remove impurities and oil. it is not

In the present invention, the separation or purification of the microparticles may be performed by a centrifuge or a filter, but is not limited thereto.

In the present invention, the washing may be selected from the same organic solvent or the group of solvents mentioned above, but is not limited thereto.

In the present invention, for the washing, distilled water, water for injection, sucrose, mannitol or sodium chloride may be used for washing after washing with an organic solvent, and an aqueous solvent selected from the group thereof, but is not limited thereto.

In the present invention, the method may further include, but is not limited to, the step of reducing the particle size using a particle size reduction equipment after redispersing the purified microparticles in the aqueous phase.

In the present invention, the redispersed aqueous phase may be an aqueous solvent in which at least one selected from the group consisting of distilled water, water for injection, sucrose, mannitol and sodium chloride is dissolved, but is not limited thereto.

In the present invention, the particle size reduction equipment may be selected from a high pressure homogenizer, a bead mill, a roll mill, and a group thereof, but is not limited thereto.

In the present invention, the execution time of the step of reducing the particle size to the nano level can be flexibly adjusted according to the amount of nanoparticles, and in general, the grinding time is extended as the amount of nanoparticles increases.

The method for preparing nanoparticles of the present invention may specifically include one or more of the following steps, or may consist of the following steps, but is not limited thereto:

a) dissolving one or more anionic polymers in an aqueous phase;

b) preparing a first solution to which the aqueous phase of step a) was added while stirring the oil phase using a homogenizer;

c) adding a second solution in which a nonionic surfactant is dissolved in an aqueous phase to the solution of b);

d) forming an emulsion while stirring the solution of c) using a homogenizer;

e) forming microparticles by adding a crosslinking agent separately dissolved in an aqueous phase to the d) emulsion;

f) further stirring in step e),

g) allowing the solution of step f) to stand still to separate the layers;

h) separating the microparticles from the oil phase;

i) extracting and/or removing residual oil and side reactants by adding an organic solvent to a solution containing microparticles;

j) separating and/or removing the residual organic solvent from the microparticles using an aqueous solution;

k) diluting the microparticles in an aqueous phase;

l) preparing nanoparticles by reducing the particle size of microparticles diluted in an aqueous solution using a high-pressure homogenizer, bead mill or roll mill, and

m) Concentrating the nanoparticles dispersed in the aqueous solution using centrifugation or ultrafiltration.

Steps a) to c) may be performed in any suitable order.

In addition, the steps are not necessarily limited to the order of description.

In the present invention, the oil phase may be selected from the group consisting of mineral oil, vegetable oil, medium chain triglycerides and mixtures thereof, but is not limited thereto.

In the present invention, the mineral oil is also called mineral oil, is a by-product generated in the process of refining crude oil, and is an oil containing alkane and paraffin as main components.

In the present invention, the vegetable oil may be oil derived from nuts, seeds, or grains, and may include, for example, peanut oil, soybean oil, coconut oil, or olive oil.

In the present invention, the medium-chain triglyceride is a representative substitute prepared by hydrolyzing palm oil and palm oil, then fractionating caprylic acid and capric acid, and esterifying (or bonding) this with glycerol again. it is fat It is a medium-chain fatty acid with usually 8 to 10 carbon atoms and has a small molecular structure.

In the present invention, the nonionic surfactant is polyvinyl alcohol (Polyvinyl Alcohol), polyalkylene glycol (polyalkylene glycol), polyvinyl pyrrolidone (Polyvinyl Pyrrolidone), alkyl polyglycoside (alkyl polyglycoside), t- octylphenoxy t-octylphenoxy polyethoxy ethanol, poloxamer, polysorbate, poly(N-vinylacetamide), polyvinyl butyral ) and may be selected from the group consisting of mixtures thereof, but is not limited thereto.

In the present invention, the polyalkylene glycol can be used without limitation, a conventional polyalkylene glycol series known in the art, it is preferable to use a polyethylene glycol series.

In the present invention, the poloxamer is a nonionic triblock copolymer in which hydrophilic ethylene oxide is bonded to both ends with a hydrophobic propylene oxide as the center, and has a temperature-sensitive feature, so that sol and The conversion of gel is possible, and the properties of the poloxamer vary according to the ratio of polyoxypropylene and polyoxyethylene. The poloxamer is poloxamer 101, poloxamer 105, poloxamer 105 benzoate, poloxamer 108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 182 dibenzoate, poloxamer Poloxamer 183, Poloxamer 184, Poloxamer 185, Poloxamer 188, Poloxamer 212, Poloxamer 215, Poloxamer 217, Poloxamer 231, Poloxamer 234, Poloxamer 235, Poloxamer 237, Poloxamer 238, Poloxamer 282 , poloxamer 284, poloxamer 288, poloxamer 331, poloxamer 333, poloxamer 334, poloxamer 335, poloxamer 338, poloxamer 401, poloxamer 402, poloxamer 403 and poloxamer 407 However, the present invention is not limited thereto.

In the present invention, the alkyl polyglycosides are, for example, C _{8 -22} alkyl glycosides, more specifically caprylyl glucoside, coco-glucoside, decyl glucoside, lauryl glucoside, methyl coco glucoside, and myristyl glucoside. It may be selected from the group consisting of, but is not limited thereto.

In the present invention, the organic solvent may be one or more selected from the group consisting of alkyl alcohols, ketones, acetonitrile, tetrahydrofuran, and mixtures thereof, but is not limited thereto.

The alkyl alcohol may be an alcohol having 1 to 6 carbon atoms, for example, methanol, ethanol, alcohol, propanol, butanol, pentanol, hexanol, but is not limited thereto.

The ketones may be an organic solvent having a chemical formula of RCOR', and may be acetone, methyl ethyl ketone, methyl butyl ketone, cyclohexanone, methyl isobutyl ketone, diisobutyl ketone, etc., but is not limited thereto.

In addition, the present invention provides a method for preparing the composition for treating vascular embolism and cancer, comprising the following steps.

Forming an emulsion by mixing a solution in which an aqueous phase in which an anionic polymer is dissolved in an oil phase; and a solution in which a nonionic surfactant is dissolved in the aqueous phase;

forming microparticles by adding an aqueous solution of a trivalent metal compound salt to the emulsion;

preparing nanoparticles by reducing the particle size to a nano level using at least one selected from the group consisting of a high pressure homogenizer, a bead mill and a roll mill for the microparticles; and

mixing the cationic drug with the nanoparticles.

The mixing of the cationic drug with the nanoparticles may be performed by treating ultrasonic waves, but is not limited thereto.

The method for preparing the composition for treating vascular embolism and cancer may further include mixing the mixed composition of the nanoparticles and the cationic drug with the embolic material, but is not limited thereto.

The mixing with the embolic material may be performed using a mixing method using a 3-way cock, a method using ultrasonic waves, or the like, but is not limited thereto.

The term “ultrasound” used in the present invention refers to a sound wave that exceeds a frequency of 16 Hz to 20 kHz, which is a frequency of sound waves that can be generally heard by the human ear, and high-intensity focused ultrasound is continuous and high-intensity ultrasonic energy. By introducing focused ultrasound provided to the focal point, instantaneous thermal effect (65-100° C.), cavitation effect, mechanical effect, and sonochemical effect can be produced depending on energy and frequency. Ultrasound is harmless when passing through human tissues, but the high-intensity ultrasound that forms a focus generates enough energy to cause coagulation necrosis and thermal cauterization regardless of the type of tissue. In the present invention, the ultrasonic wave refers to a sound wave having a frequency greater than 16 Hz to 20 kHz, which is an audible frequency range.

Throughout the specification of the present invention, when a part "includes" a certain component, it means that other components may be further included, rather than excluding other components, unless otherwise stated. The terms "about", "substantially", etc. to the extent used throughout the specification of the present invention are used in or close to the numerical value when the manufacturing and material tolerances inherent in the stated meaning are presented, and the present invention It is used to prevent an unconscionable infringer from using the disclosure in which exact or absolute figures are mentioned to help the understanding of the

Throughout the specification of the present invention, the term "combination of these" included in the expression of the Markush form means one or more mixtures or combinations selected from the group consisting of the components described in the expression of the Markush form, It means to include one or more selected from the group consisting of components.

In this specification (especially in the claims), the use of the term “above” and similar referential terms may be used in both the singular and the plural. In addition, when a range is described, individual values within the range are included (unless there is a description to the contrary), and each individual value constituting the range is described in the detailed description. Finally, the steps constituting the method may be performed in an appropriate order unless the order is explicitly stated or there is no description to the contrary. It is not necessarily limited to the order of description of the above steps. The use of all examples or exemplary terms (eg, etc.) is merely for describing the technical idea in detail, and the scope is not limited by the examples or exemplary terms unless limited by the claims. In addition, those skilled in the art will appreciate that various modifications, combinations, and changes can be made in accordance with design conditions and factors within the scope of the appended claims or their equivalents.

Terms such as first, second, etc. may be used to describe various elements, but the elements should not be limited by the terms. The above terms are used only for the purpose of distinguishing one component from another. For example, without departing from the scope of the present invention, a first component may be referred to as a second component, and similarly, a second component may also be referred to as a first component. and/or includes a combination of a plurality of related listed items or any of a plurality of related listed items.

Since the present invention can apply various transformations and can have various embodiments, specific embodiments are illustrated in the drawings and described in detail in the detailed description. However, this is not intended to limit the present invention to specific embodiments, it should be understood to include all modifications, equivalents and substitutes included in the spirit and scope of the present invention. In describing the present invention, if it is determined that a detailed description of a related known technology may obscure the gist of the present invention, the detailed description thereof will be omitted.

Hereinafter, preferred examples are presented to help the understanding of the present invention. However, the following examples are only provided for easier understanding of the present invention, and the contents of the present invention are not limited by the following examples.

[Example]

Example 1. Test for confirming the reactivity of a polymer and a crosslinking agent

To compare the reactivity between the anionic polymer and calcium chloride, the reactivity was tested by adding calcium chloride in the presence of CMC (Carboxymethyl cellulose).

Example 1-1. Reactivity Test 1

In a 20mL container, 2mL of 0.2% CMC and 2mL of 0.2% carboxymethyl dextran sodium (hereinafter, CMD) were added, and 0.5mL of 10% calcium chloride was added while stirring. No solid was formed upon checking for 1 hour.

Example 1-2. Reactivity Test 2

Reactivity was confirmed by increasing the concentration and performing the test in the same manner as in <Reactivity Test 1> for each composition in Table 1 below.

As shown in Figure 1, there was no change in the case of composition 1, and in the case of compositions 2 and 3, it was changed to a suspension.

In addition, as shown in FIG. 2 , as a result of confirming an optical microscope analysis image of the reaction solid of composition 2 in Table 1, it was confirmed that the reaction solid was not particleized but gelled.

According to the above results, it was confirmed that calcium chloride is not suitable as a crosslinking agent for preparing nanoparticles.

Reactivity Test 2 Composition number CMC CMD CaCl ₂ microparticles
formed or not composition 1 - 20% 5% with clear solution
not formed composition 2 7% - 5% As a suspension, as a result of microscopic examination, no particles were formed, gelation composition 3 7% 20% 5% As a result of microscopic examination as a suspension, no particles were formed and gelled.

Example 2. Preparation of microparticles using W/O emulsion

CMC, iron chloride (FeCl ₃ ) solution and DS (dextran sulfate) powder were prepared according to the composition ratios in Table 2 below.

First, the DS powder is dissolved in the CMC solution, mixed with a 1% solution of polyvinyl alcohol (hereinafter PVA) at room temperature, and then added dropwise to the medium chain triglyceride (MCT) oil used as an oil phase, and a sonicator was used to prepare an emulsion. FeCl ₃ was added dropwise to the emulsion and further stirred to prepare particles. In order to obtain the formed particles, centrifugation was performed at 4° C., 15,000 rpm for 10 minutes, and insoluble matter and MCT oil were removed using ethanol. After separation using a centrifuge under the same conditions sequentially using ethanol and purified water, it was finally redispersed in 2 mL of purified water.

Test composition and conditions number CMC DS PVA Sonication
time W/O
Ratio FeCl ₃ bridge time composition 1 0.50%, 0.5mL 10mg 1%, 0.5mL 90s 1: 20 0.50% 2hr composition 2 0.50%, 0.5mL 10mg 1%, 0.5mL 90s 1:5 0.40% 2hr composition 3 0.50%, 0.5mL 10mg 1%, 0.5mL 180s 1:20 0.40% 2hr composition 4 0.10%, 0.5mL 10mg 1%, 0.5mL 90s 1:40 0.40% 2hr composition 5 0.10%, 0.5mL 10mg 1%, 0.5mL 90s 1:20 0.40% 2hr composition 6 0.50%, 0.5mL 10mg 1%, 0.5mL 90s 1:40 0.40% 2hr

As a result, as the CMC concentration increased and the sonication time increased, particle formation was well achieved.

Example 3. Confirmation of yield according to the preparation of microparticles using W/O emulsion

For scale-up, a homogenizer was used instead of an ultrasonic disperser. Particles were prepared according to the composition ratios in Table 3 below by the same preparation method at room temperature using a homogenizer (rpm: 17,000), and the yields according to each composition ratio were compared. Finally, each of the redispersed suspensions was lyophilized to measure the mass after drying.

As shown in FIG. 3 , through the image of the solid produced through composition 2 in Table 3, it was found that particles were formed when iron chloride was used rather than when calcium chloride was used.

As shown in Table 3, it was confirmed that the highest yield was obtained when CMC and DS were mixed in a mass ratio of 2:1.

Test composition, conditions, yield and yield number CMC DS PVA
(mass%) Homogenization
hour W/O
Ratio crosslinking agent
(mass%) bridge
hour yield transference number composition 1 1%, 100 mL,
(1 g) 2g 2%, 100mL 10min 1: 4 2.5% FeCl ₃ , 100mL 30min 1.08g 36.0% composition 2 1%, 100mL, (1g) 0.5g 2%, 100mL 10min 1: 4 2.5% FeCl ₃ , 100mL 30min 0.83g 79.0% composition 3 1%, 100mL, (1g) 1 g 2%, 100mL 10min 1: 4 2.5% FeCl ₃ , 100mL 30min 1.01g 50.5% composition 4 2%, 100mL, (2g) 0.5g 2%, 100mL 10min 1:4 2% AlCl ₃ , 100mL 30min 1.23g 49%

(However, the yield excludes the crosslinking agent content)

Example 4. Preparation of nanoparticles through additional nanoprocessing after preparation of microparticles using W/O emulsion

Microparticle production was implemented in the following way. To prepare an aqueous solution, 2 g of PVA and 1 g of CMC were each dissolved in 100 mL of distilled water. Then, 0.5 g of DS was weighed, added to the CMC solution, and then dissolved. To prepare the crosslinking agent solution, 0.5 g of iron (III) chloride (FeCl ₃ ) was dissolved in 100 mL of distilled water.

To prepare a W/O emulsion, 800 mL of MCT oil was filled in a 2L beaker, and all the solutions of the water phase were added while stirring at 17,000 rpm at room temperature using a homogenizer. After stirring for 10 minutes under the same conditions, the crosslinking agent solution was added dropwise and stirred for an additional 30 minutes.

Microparticles were isolated using the following experimental method: The reaction solution was transferred to a separatory funnel and allowed to stand for 2 hours. The lower layer solution (aqueous phase) in which a yellow solid was present in a separatory funnel was collected and a yellow particle pellet was generated using a centrifuge. The supernatant was discarded and the white material was removed by dissolving it with ethanol. At this time, care was taken not to affect the pellet in the lower layer. Ethanol 15mL was added, and the pellet was redispersed using a vortex and ultrasonic disperser, and repeated until no lumps were seen. Then, in addition to ethanol, the washing process was sequentially repeated with distilled water and sucrose (5%) solution to obtain microparticle particles. Finally, it was redispersed in a 5%-sucrose solution.

For the preparation of nanoparticles, a bead mill (Minicer, Netzsch) was used. The washed particles were diluted in 5%-sucrose solution to prepare an amount of about 500 mL. Small particles were prepared by milling at a pump speed of 20 rpm, a flow rate of 5 m/s, and about 10° C. using a bead of 0.2 mm in a bead mill equipment. After replacing the bead with 0.1mm, it was additionally milled at a pump speed of 10rpm, a flow rate of 4m/s, and the same temperature to obtain particles having a size of Ave.146.6nm (PDI: 0.145).

As shown in FIG. 4 , as a result of dynamic light scattering (DLS) measurement, the particle distribution was found to be 50 nm to 460 nm.

In addition, as shown in FIG. 5 , it was confirmed that nano-sized particles were well generated through the nano process.

Example 5. Preparation and dissolution test of nanoparticles loaded with doxorubicin hydrochloride

Doxorubicin hydrochloride was completely dissolved in a 5%-sucrose solution at a concentration of 25 mg/mL. Put the completely dissolved doxorubicin hydrochloride sucrose solution into 1.25 mL of a 5%-sucrose solution in which 60 mg of nanoparticles are dispersed, adjust the ratio of doxorubicin hydrochloride: particle = 25 mg: 60 mg, and after initial 1 minute ultrasonic treatment (bath type sonication) about 30 minutes during further mixing.

500 μL of the doxorubicin hydrochloride-loaded nanoparticle suspension was placed on a Cellu Sep membrane (MW: 15,000, Width: 32 mm, Wall thickness: 24 μm), and both sides were closed with clips. Buffer (PVA 0.4%, Tween 0.1% in Lactic acid pH=2.7, 37°C) was placed in 50mL in a vial and stirred at 200 rpm, and the temperature was raised to 37°C. The membrane sample was added and a dissolution test was performed. The amount of elution was confirmed by measuring the absorbance of the sample taken for each point with a UV spectrometer (wavelength: 475 nm).

As a result, as shown in FIG. 6 , the elution amount of doxorubicin was about 70%, which was excellent.

Example 6. in vitro Cytotoxicity assessment

In order to evaluate the toxicity of the prepared nanoparticles, a viability analysis was performed on Huh7 liver cancer cells. Three groups of doxorubicin hydrochloride (dox), doxorubicin-loaded particles (032d), and doxorubicin-free particles (032) were evaluated.

As shown in FIG. 7 , it was confirmed that in the case of particles loaded with the same drug as doxorubicin hydrochloride itself, the cancer cell killing effect was shown in a concentration-dependent manner. was not seen

Example 7. Preparation of mixed emulsion with Lipiodol and confirmation of microcatheter passage

In a vial containing 50 mg of doxorubicin hydrochloride (Ildong Adriamycin RDF), add 1.25 mL of OmnipaQ 300 stock (GE Healthcare) to dissolve the drug, take the entire amount using a syringe, and 60 mg of nanoparticles in 2 mL of 5%-sucrose solution A suspension was prepared in which the drug was loaded onto the nanoparticles by mixing in the dispersed solution. Then, 10 mL of Lipiodol ultra solution (Guerbet Korea) was prepared in a separate syringe. The two solutions were mounted on a 3-way cock and the syringe was alternately pushed to prepare an emulsion. An image of the formed emulsion is shown in FIG. 8 .

The microcatheter was connected to the last side of the three-way cock containing the emulsion prepared above and passed by pressing the syringe. The microcatheter passage test was compared with the emulsion prepared by replacing the 5%-sucrose solution with the 15%-mannitol solution in the same manner.

As a result, as shown in Figure 9, both cases passed through the microcatheter.

Therefore, it was confirmed that the emulsion prepared by the method of the present invention can be used for embolization through the microcatheter.

The above description of the present invention is for illustration, and those of ordinary skill in the art to which the present invention pertains can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.

Claims (18)

nanoparticles comprising an anionic polymer and a trivalent metal compound salt; and
A composition for the treatment of cancer comprising a cationic drug for cancer treatment as an active ingredient,
The composition is used for vascular embolization,
The anionic polymer comprises carboxymethyl cellulose and dextran sulfate,
The trivalent metal compound salt is iron (III) chloride or aluminum chloride,
The nanoparticles are characterized in that for cationic drug delivery, the composition.
nanoparticles comprising an anionic polymer and a salt of a trivalent metal compound; and
A composition for cationic drug delivery comprising a cationic drug as an active ingredient,
The composition is used for vascular embolization,
The anionic polymer includes carboxymethyl cellulose and dextran sulfate,
The trivalent metal compound salt is iron (III) chloride or aluminum chloride,
The cationic drug is characterized in that the nanoparticles are loaded, the composition.
delete The method of claim 1,
The carboxymethyl cellulose and dextran sulfate are 0.5 to 20: A composition, characterized in that it is included in a mass ratio of 1.
delete According to claim 1,
The cationic drug is doxorubicin, procainamide, digoxin, quinidine, trimethoprim, cimetidine, vancomycin, irinotecan, At least one selected from the group consisting of daunorubicin, epirubicin, diphenhydramine, memantine, oxycodone, pyrilamine and tramadol Characterized in that, the composition.
According to claim 1,
The cationic drug is characterized in that loaded into the nanoparticles, composition.
According to claim 1,
The composition is characterized in that the emulsion formulation, the composition.
According to claim 1,
The cationic drug and nanoparticles are characterized in that included in a mass ratio of 1 to 1 to 10, the composition.
The method of claim 1,
The composition, characterized in that it further comprises an embolic material.
11. The method of claim 10,
The composition, characterized in that the embolic material is iodized oil.
12. The method of claim 11,
The iodized oil is at least one selected from the group consisting of poppy fruit-derived iodized oil, soybean-derived iodized oil and ethiodol (ethiodol), the composition.
According to claim 1,
The composition, characterized in that the nanoparticles have a diameter of 10 to 500 nm.
Forming an emulsion by mixing a solution in which an aqueous phase in which an anionic polymer is dissolved in an oil phase; and a solution in which a nonionic surfactant is dissolved in the aqueous phase;
forming microparticles by adding an aqueous solution of a trivalent metal compound salt to the emulsion; and
Preparation of nanoparticles containing an anionic polymer and a trivalent metal compound salt, comprising reducing the particle size to a nano level by using at least one selected from the group consisting of a high pressure homogenizer, a bead mill and a roll mill for the microparticles As a method,
The anionic polymer includes carboxymethyl cellulose and dextran sulfate,
The method, characterized in that the trivalent metal compound salt is iron (III) chloride, or aluminum chloride.
delete 15. The method of claim 14,
The method, characterized in that the oil phase is selected from the group consisting of mineral oil, vegetable oil, medium chain triglycerides and mixtures thereof.
15. The method of claim 14,
The nonionic surfactant is polyvinyl alcohol, polyalkylene glycol, polyvinyl pyrrolidone, alkyl polyglycoside, t-octylphenoxy polyethoxy Ethanol (t-octylphenoxy polyethoxy ethanol), poloxamer (poloxamer), polysorbate (polysorbate), poly (N-vinylacetamide) (poly (N-vinylacetamide)), polyvinyl butyral (polyvinyl butyral) and their A method, characterized in that it is selected from the group consisting of mixtures.
Forming an emulsion by mixing a solution in which an aqueous phase in which an anionic polymer is dissolved in an oil phase; and a solution in which a nonionic surfactant is dissolved in the aqueous phase;
forming microparticles by adding an aqueous solution of a trivalent metal compound salt to the emulsion;
preparing nanoparticles by reducing the particle size to a nano level using at least one selected from the group consisting of a high pressure homogenizer, a bead mill and a roll mill for the microparticles; and
A method for preparing the composition for treating cancer according to claim 1, which is used for vascular embolization, comprising mixing a cationic drug with the nanoparticles,
The anionic polymer includes carboxymethyl cellulose and dextran sulfate,
The method, characterized in that the trivalent metal compound salt is iron (III) chloride, or aluminum chloride.

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